1. Field of the Invention
The present invention relates to a transition-metal-free aerobic oxidation method for primary and secondary alcohols towards the corresponding aldehydes and ketones at low pressures in the presence of a stable free nitroxyl radical.
2. Discussion of the Background
The oxidation of alcohols to the corresponding aldehydes, ketones or acids certainly represents one of the most important functional group transformations in organic synthesis and there are numerous methods reported in the literature (Sheldon, R. A., Kochi, J. K. Metal-Catalysed Oxidations of Organic Compounds; Academic Press: New York, 1981; Hudlicky, M. Oxidations in Organic Chemistry; American Chemical Society: Washington D.C. 1990).
However, relatively few methods describe the selective oxidation of primary or secondary alcohols to the corresponding aldehydes and ketones and most of them traditionally use a stoichiometric terminal oxidant such as chromium oxide (Holum, J. R. J. Org. Chem. 1961, 26, 4814–4816), dichromate (Lee, D. G; Spitzer, U. A. J. Org. Chem. 1970, 35, 3589–3590), manganese oxide (Highet, R. J.; Wildman, W. C. J. Am. Chem. Soc. 1955, 77, 4399–4401) and osmium or ruthenium as primary oxidants (Murahashi, S.-I; Naota, T. J. Synth. Org. Chem. Jpn. 1988, 46, 930–942).
A convenient procedure for the oxidation of primary and secondary alcohols is reported by Anelli and co-workers (J. Org. Chem., 1987, 52, 2559). Accordingly, the oxidation has been carried out in CH2Cl2—aqueous buffer of pH 8.5–9.5 utilizing 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as a catalyst and KBr as a co-catalyst. The terminal oxidant in this system is NaOCl. A major disadvantage of using sodium hypochlorite or any other hypohalite as stoichiometric oxidant is that per mol of alcohol oxidized during the reaction one mole of halogenated salt is formed. Furthermore, the use of hypohalites very frequently leads to the formation of undesirable halogenated by-products thus necessitating further purification of the oxidation product. Extensive review of methods based on the TEMPO based oxidations is found elsewhere (Synthesis, 1996, 1153–1174; Topics in Catalysis 2004, 27, 49–66; Acc. Chem. Res. 2002, 35, 774–781).
U.S. Pat. No. 5,821,374 discloses the use of N-chloro compounds such as N-chloro-4-toluenesulfonamide sodium salt as an oxidant in the TEMPO catalyzed oxidation of primary alcohols to aldehydes. The major drawback of this method is the use of large amounts of solvents and the toxicity of the N-chlorinated aromatics used as oxidants.
In recent years, a lot of efforts have been spent on developing both selective and environmentally friendly oxidation methods using either air or oxygen as primary oxidants and catalyst systems, based on stable nitroxyl radicals as catalysts and transition metal salts as co-catalysts. The most commonly used co-catalysts are (NH4)2Ce(NO3)6 (Kim, S. S.; Jung, H. C. Synthesis 2003, 14, 2135–2137), CuBr2-2,2′-bipyridine complex (Gamez, P; Arends, I. W. C. E.; Reedijk, J.; Sheldon, R. A. Chem. Commun. 2003, 19, 2414–2415), RuCl2(PPh3)3 (Inokuchi, T.; Nakagawa, K.; Torii, S. Tetrahedron Letters 1995, 36, 3223–3226 and Dijksman, A.; Marino-Gonzalez, A.; Payeras, A. M.; Arends, I. W. C. E.; Sheldon, R. A. J. Am. Chem. Soc. 2001, 123, 6826–6833), Mn(NO3)2—Co(NO3)2 and Mn(NO3)2—Cu(NO3)2 (Cecchetto, A.; Fontana, F.; Minisci, F.; Recupero, F. Tetrahedron Letters 2001, 42, 6651–6653), and CuCl in ionic liquid [bmim][PF6] (Imtiaz, A. A; Gree, R. Organic Letters 2002, 4, 1507–1509).
However, from an economic and environmental point of view the above mentioned oxidation methods suffer from one major drawback. They depend on substantial amounts of expensive and/or toxic transition metal complexes and some of them require the use of halogenated solvents such as dichloromethane, which makes them unsuitable for industrial scale production. Very recently, Hu et al. disclosed a process for aerobic oxidation of primary and secondary alcohols utilizing a TEMPO based catalyst system, free of any transition metal co-catalyst (Liu, R.; Liang, X.; Dong, C.; Hu, X. J. Am. Chem. Soc. 2004, 126, 4112–4113). In this process, the authors employed a mixture of TEMPO (1 mol %), sodium nitrite (4–8 mol %) and bromine (4 mol %) as the active catalyst system. The oxidation takes place at temperatures between 80–100° C. and at an air pressure of 4 bar. However, this process is only successful with activated alcohols. If benzyl alcohol is used, quantitative conversion is achieved after 1–2 h of reaction time. In the case of non-activated aliphatic alcohols (such as 1-octanol) or cyclic alcohols (such as cyclohexanol) the air pressure needs to be raised up to 9 bar and 3 to 4 h of reaction time were necessary to reach complete conversion. Disadvantageously, this new oxidation procedure again depends on dichloromethane as a solvent, which is a major obstacle for an industrial application of the method. Furthermore, elemental bromine as a co-catalyst is rather difficult to handle on a technical scale due to its high vapor pressure, toxicity and severe corrosion when applied in standard steel apparatus. Other disadvantages of this method are the rather low substrate concentration in the solvent used and the observed formation of bromination by-products.